What Clinicians Should Know About Hepatitis C Virus Clinicians Should Know About Hepatitis C Virus Michael S. Saag, MD Associate Dean, Global Health Professor of Medicine Director,

What Clinicians Should Know

About Hepatitis C Virus

Michael S. Saag, MDAssociate Dean, Global Health

Professor of MedicineDirector, Center for AIDS Research

University of Alabama at BirminghamBirmingham, Alabama

FINAL AS OF: 11/15/17

Slide 3 of 55

Learning Objectives

After attending this presentation,

learners will be able to: Describe the genotypes of HCV and how they relate

to treatment effects

Recognize how to stage HCV infection and why it is important to accurately stage

Recall the clinical presentation of advanced liver disease (cirrhosis)

Describe emerging treatments of HCV and how the changing landscape will impact treatment decisions in the near future

Identify new changes to the HCV Guidelines (Sept 2017)

Slide 5 of 55

Which test most accurately stage liver fibrosis?

1. Fibroscan

2. Fibrosure

3. APRI

4. Liver biopsy

5. Liver percussion

Fibro

scan

Fibro

sure

APRI

Liver

bio

psy

Liver

per

cuss

ion

27%

9%

0%

64%

0%

Louisville, Kentucky, November 17, 2017 1

Slide 7 of 55

What percent of persons with chronic HCV infection develop

cirrhosis over 30 years?

1. 0 – 5%

2. 6% – 20%

3. 21% – 50%

4. 51% – 75%

5. >75%

0 –

5%

6%

– 2

0%

21% –

50%

51% –

75%

>75

%

0%

23% 23%

15%

38%

Slide 9 of 55

What is the most common genotype of HCV in the United

States?

1. Genotype 1

2. Genotype 2

3. Genotype 3

4. Genotype 4

5. Genotype 5–6

Genotype

1

Genotype

2

Genotype

3

Genotype

4

Genotype

5–6

93%

0% 0%0%7%

Slide 10 of 55

Objectives

Epidemiology

Natural History

Staging

Genome and Drug Targets

Viral Kinetics With Therapy

Current Treatments

What Does SVR Really Mean?


Slide 11 of 55

Objectives

Epidemiology

Natural History

Staging



Current Treatments


Slide 12 of 55

HCV Research Timeline

Moradpour Nature Reviews 2007; 5:453-463

AIDS

1982

HIV

1984

AZT

1987

Slide 13 of 55

HCV Worldwide

170 million infected

Highest Asia & Africa

Egypt > 15%

USA 1.6%– 3-4 million infected

www.cdc.gov


Slide 14 of 55

Worldwide prevalence of each HCV genotype by GBD

HCV genotype 1 (83.4 million cases: 46.2%)- one-third of which are in East Asia.

Genotype 3 (54.3 million: 30.1%); genotypes 2, 4, and 6 (22.8%); genotype 5 <1%.

While genotypes 1 and 3 dominate in most countries irrespective of economic Status: largest proportions of genotypes 4 and 5 are in lower-income countries.

Slide 15 of 55

The Treatment Cascade of HCV infection in

the US:~3 – 4 million persons infected

Adapted from Holmberg et al. NEJM 2013

0%25%50%75%

100% 100%

50%38%

23%11% 6%

Slide 16 of 55

Future Burden of Hepatitis C Related Morbidity and

Mortality in the US

Markov model of health outcomes

– Of 2.7 M HCV infected persons in primary care

1.47 M will develop cirrhosis

350,000 will develop liver cancer

897,000 will die from HCV-related complications

Rein D, et al. Dig Liver Dis 2010.

05000

10000150002000025000300003500040000

2010

2013

2016

2019

2022

2025

2028

2031

2034

2037

2040

2043

2046

2049

2052

2055

2058

Deaths

DCC

HCC

Nu

mb

er


Slide 17 of 55

Objectives

Epidemiology

Natural History

Staging



Current Treatments


Slide 18 of 55

Resolved

Stable

Slowly

Progressive

Transplant/Death

~20%

~15% ~85%

~3%-4%/yr

~80%

~75%

~ 20-year progression rate may beaccelerated with HIV, HBV,

alcohol, and steatosis1,2

Exposure(Acute Phase)

Chronic

Cirrhosis

~4%/yr~6%/yr

ESLD HCC

10 20 30Time(yrs)

5-year survival in patients with HCC is <5%*

ESLD: end-stage liver disease

*NIH Consens Statement. June 10-12, 2002;19(3):1-46. NIH Consens Statement. March 24-26, 1997;15(3):1-41.

1. Di Bisceglie AM. Hepatology. 2000;31(4):1014-1018. 2. Bialek SR, Terrault NA. Clin Liver Dis. 2006;10(4):697-715.

Natural History of HCV Infection

Slide 19 of 55

Objectives

Epidemiology

Natural History

Staging



Current Treatments



Slide 20 of 55

Fibrosis/Cirrhosis

Slide 25 of 55

Objectives

Epidemiology

Natural History

Staging



Current Treatments


Slide 26 of 55

Translation

HCV NS proteins

NS2

Polyprotein

processing

NS3

NS4B

NS5A NS5B

HCV RNA

Fusion and

uncoating

RNA

replication

NS5A

CypA

NS5B

NS2

NS3

NS4B

Viral

assembly

Transport and

release

NS3/4A protease inhibitors

NS5A inhibitors

NS5B polymerase inhibitors

NS5A inhibitors

Potential Therapeutic Targets in the HCV

Replication Cycle

Adapted from slide courtesy Ray Chung


Slide 27 of 55

NUCLEOSIDEINHIBITORS

Non-NUCLEOSIDEINHIBITORS

“NS5A”INHIBITORS

PROTEASE INHIBITORS

Slide 28 of 55

Suffixes Matter!

- --- PREVIR (Protease / NS3-4a)

- --- ASVIR (NS5a)

- --- BUVIR (NS5b)

Slide 29 of 55

Agents and Regimens: Fall 2017

Antiviral

NS3 NS5ANon-Nuc

NS5BNuc

NS5B

Ledipasvir/sofosbuvir FDC

Paritaprevir/r/ombitasvir FDC + dasabuvir

Simeprevir + sofosbuvir

Glecaprevir / pibrentasvir FDC

Sofosbuvir + daclatasvir

Elbasvir/grazoprevir FDC

Velpatasvir/sofosbuvir FDCVelpat/ Sof / voxilaprevir FDC


Slide 30 of 55

Objectives

Epidemiology

Natural History

Staging



Current Treatments


Slide 31 of 55

On Treatment Viral Kinetics

2 log decline

LOD

Slide 32 of 55

Objectives

Epidemiology

Natural History

Staging



Current Treatments



Slide 33 of 55

Chronic HCV prior SOC

Pegylated IFN + RBV

48-72 weeks

Significant AEs

Response > GT 2/3SV

R, %

Fried MW, NEJM 2002

Manns MP, Lancet 2001

Slide 34 of 55

Antiviral HCV treatments

(FDA-approved as of September, 2017)

Monotherapies

IFN-2a

IFN-2b

PEG-IFN 2a

PEG-IFN 2b

– IFN-2a + Ribavirin

– IFN-2b + Ribavirin

–PEG-IFN 2a + Ribavirin*

–PEG-IFN 2b + Ribavirin

– PEG-IFN + ribavirin plus either:

– Boceprevir (GT1)

– Telaprevir (GT1)

– Simeprevir (GT1)

–In combination with other

agents:

–Sofosbuvir

• Combination Therapies

Simeprevir + Sofosbuvir (GT1)

Paritaprevir / ritonavir / ombitasvir

(FDC) + dasabuvir (GT1)

Paritaprevir / ritonavir/ ombitasvir

(FDC) (GT4)

–Daclatasvir + Sofosbuvir

–(GT1,3)*§

Elbasvir + Grazoprevir

–(GT 1, 4)Velpatasvir / Sofosbuvir FDC

Voxilaprevir / Velpatasvir /

Sofosbuvir FDC

Glecaprevir / Pibrentasvir FDC

Ledipasvir + Sofosbuvir

(FDC, GT1,4,5,6)

Pangenotypic Regimens

(GT 1 – 6 )

Slide 35 of 70

Slide 35 of 55

Sofosbuvir plus Daclatasvir for GT1

41n=44 20 2141

No documented virologic failures. All failures due to missing sample/lost to follow-up or re-infection.


Slide 36 of 70

Slide 36 of 55

Slide 36 of 70

Slide 37 of 55

Predictors of relapse to sofosbuvir-

based regimens

RBVSOF

RB

VSO

F12 week

FISSION

POSITRON

FUSION

VALENCE

n=285

24 week

VALENCE

n=247

PE

G RB

VSO

F12 week

ATOMIC

NEUTRINO

n=339

Who will do poorly with currently-

available SOF-based regimens?

Foster et al. EASL 2014 Abstract 66

GT177%

GT29%

GT310%

GT44%

Slide 38 of 55


based regimens

RBVSOF

RB

VSO

F12 week

FISSION

POSITRON

FUSION

VALENCE

n=285

24 week

VALENCE

n=247

PE

G RB

VSO

F12 week

ATOMIC

NEUTRINO

n=339





Slide 39 of 55


based regimens

RBVSOF

RB

VSO

F12 week

FISSION

POSITRON

FUSION

VALENCE

n=285

24 week

VALENCE

n=247

PE

G RB

VSO

F12 week

ATOMIC

NEUTRINO

n=339




Six factors associated with relapse:

Treatment-experienced

IL28B non-CC

Male sex

Weight > 75 kg

Cirrhosis

High viral load >800,000 IU/mL

Slide 40 of 55

Updated

Guidelines

https://www.hcvguidelines.org

Slide 42 of 55

Which of the following statements is true of FDA approval of

glecaprevir/pibrentasvir?

1. It is an 8 week regimen only in patients without cirrhosis

2. It is a 12 week regimen regardless of presence of cirrhosis

3. It is an 8 week regimen only in treatment naïve patients

4. It is a 16 week regimen in patients with prior treatment experience to DAA

5. It is a single daily dosed pill

It is

an 8

wee

k reg

imen

only

..

It is

a 12

week

regi

men re

g...

It is

an 8

wee

k reg

imen

only

...

It is

a 16

week

regi

men in

p...

It is

a sin

gle d

aily d

osed p

ill

0%

50%

17%

0%

33%


https://www.hcvguidelines.org/

Slide 43 of 70

Slide 43 of 55

Glecaprevir (NS3)/pibrentasvir (NS5A)

•Co-formulated – 3 pills once daily

•Pangenotypic

•Next generation

–Active vs NS3 RAS at 80, 155, 168 and

NS5A RAS at 28, Q30, 31, 93

–A30K associated with failure in GT3

infection

•Negligible renal excretion

•Contains a protease inhibitor

•Has interaction with acid suppressing meds

Slide 44 of 55

Glecaprevir/pibrentasvir: no cirrhosis

►8 (N=828) vs 12 (N=1076) weeks

►TN and TE

–PEG, RBV, SOF

–No DAA otherwise

►Relapse <1%

►Tx emergent RAS

►TN GT3 may need 12W

►TE GT3 – may need 16 weeks

99 99 99 97100 100 10099 100 100 98 100 100 100

0

10

20

30

40

50

60

70

80

90

100

All GT 1 GT 2 GT 3 GT 4 GT 5 GT 6

8 weeks 12 weeks

Puoti et al. EASL 2017

Which of the following statements is true of FDA approval of sofosbuvir/velpatasvir/voxilaprevir?

1. It is an 8 week regimen only in patients without cirrhosis

2. It is a 12 week regimen regardless of presence of cirrhosis

3. It is an 8 week regimen regardless of prior treatment experience to DAA

4. It is approved for all genotypes across all DAA failures

It is

an 8

wee

k reg

imen

only

..

It is

a 12

week

regi

men re

g...

It is

an 8

wee

k reg

imen

reg.

..

It is

appro

ved fo

r all

genot..

.

8%

58%

0%

33%


Slide 47 of 55

Sofosbuvir/velpatasvir/voxilaprevir: 8 vs 12 weeks of SOF/VEL

►POLARIS 2

– GT 1-6 w/ and w/o cirrhosis

►POLARIS 3

– GT 3 with cirrhosis

– 2 relapses

►Pooled analysis

– N=611

►8 weeks of therapy failed non-inferiority in POLARIS-2

– 3.8% relapse

– 14 GT1a (regardless of cirrhosis)

9297 97 98 94 94 100

0

10

20

30

40

50

60

70

80

90

100

GT 1aGT 1b GT 2 GT 3 GT 4 GT 5 GT 6

Roberts et al. EASL 2017; Jacobson et al. Gastro 2017

Slide 40 of 52

Slide 48 of 55

Sofosbuvir/velpatasvir/voxilaprevirNS5A Inhibitor DAA -Experienced

►POLARIS 1

–GT 1-6 (30% GT3)

►12 weeks of therapy

– vs placebo

►Including compensated cirrhosis (46%)

►2.2% relapse

►4 GT 3 relapse – all 3a and ¾ had BL NS5A RAS

►No treatment emergent RAS

►all VF had cirrhosis (6 R, 1 VBT)

Bourliere et al. NEJM 2017

Slide 49 of 55

Does Failure = Resistance?


Slide 50 of 55

Key HCV Resistance Concepts

HCV resistance associated substitutions (RASs) can

be present without drug exposure

HCV RASs impacts treatment responses in specific

situation

HCV is resistance is NOT absolute

Patient characteristics are just (if not more) important

than RASs

Future regimens appear to obviate the need for most

resistance testing

Slide 51 of 55

Resistance Characteristics of HCV Antiviral Classes

ClassAntiviral Potency

GenotypeActivity

ResistanceBarrier

FDA Approvals

NS3 ProteaseInhibitors

+++ to ++++1, 4

(± 2, 3, 6)

Lowto

High

Simeprevir (2013)Paritaprevir (2014)Grazoprevir (2016)Voxilaprevir (2017)Glecaprevir (2017)

NS5B Nucleotide ++++ 1-6 Very High Sofosbuvir (2013)

NS5BNonnucleoside

++ 1 Low Dasabuvir (2014)

NS5A Inhibitors ++++1, 4, 6

(± 2, 3)

LowTo

High

Ledipasvir (2014)Daclatasvir (2015)Ombitasvir (2014)

Elbasvir (2016)Velpatasvir (2016)Pibrentasvir (2017)

*anticipated US FDA approvals

Slide 52 of 55

Broad Cross-Resistance With “Early Generation” NS5As

Fold Change Genotype 1a Genotype 1b

M28T Q30R L31M/V Y93H/N L31V Y93H/N

Ledipasvir 20x > 100x> 100x/

> 100x

> 1000x/

> 10,000> 100x/--

Ombitasvir > 1000x > 100x< 3x > 10,000x/

> 10,000x< 10x 20x/50x

> 100x

Daclatasvir > 100x > 1000x> 100x/

> 1000x

> 1000x/

> 10,000x< 10x 20x/50x

Elbasvir 20x > 100x> 10x > 1000x/

> 1000x< 10x > 100x/--

> 100x

Velpatasvir < 10x < 3x 20x/50x> 100x/

> 1000x< 3x < 3x/--

Pibrentasvir < 3x < 3x < 3x < 10x/< 10x < 3x < 3x/< 3x

Ruzasvir < 10x < 10x < 10x < 10x < 10x < 10x


Slide 53 of 55

Objectives

Epidemiology

Natural History

Staging



Current Treatments


Slide 54 of 55

Long-Term Follow-Up of SOF Phase 3 Studies

Median time to follow-up: 170 days (~ 24 weeks) after SVR24

Of 480 patients with SVR24 from phase 3 trials, 435 (91%) and 90 (19%) had post-treatment week 48 and 72

data, respectively Cheng W, et al. EASL 2014. P1112.

78/78 52/52 88/88 37/37 84/84 185/185 1/1

Slide 55 of 55

JAMA. 2012;308(4):370-378. doi:10.1001/jama.2012.7844


Slide 56 of 55

Clinical Benefits of SVR:

Liver Failure, HCC

Liver Failure

Live

r Fa

ilure

(%

)

Time, y

Hep

ato

cell

ula

rC

arci

no

ma

(%

)

Time, y

Hepatocellular Carcinoma

van der Meer AJ, et al. JAMA. 2012;308(24):2584–2593.

530 Europeans followed for a median 8.4 years after HCV treatment

192 (36%) achieved SVR

Slide 57 of 55

Effects of SVR on the risk of liver transplant, hepatocellular carcinoma,

death and re-infection:

meta analysis, 129 studies, 34,563 patients

Hill AASLD 2014

5-year risk of hepatocellular carcinoma

by SVR

General: 21 stud

n=12,496Avg. FU=6.1 years

Cirrhotic: 18 stud


HIV/HCV: 3 studies


5-year risk of death (all-cause)

by SVR

Gen 18 stud


Cirr 9 stud


HIV/HCV: 5 stud


Slide 58 of 55


Documents

What Clinicians Should Know About Hepatitis C Virus Clinicians Should Know About Hepatitis C Virus Michael S. Saag, MD Associate Dean, Global Health Professor of Medicine Director,